Diet-stress interactions in gut barrier dysfunction and metabolic inflammation

The intestinal barrier is a dynamic host-microbe interface that contributes to metabolic homeostasis. Chronic psychological stress and adverse dietary patterns can each disturb microbiota, mucus, junctional, and inflammatory processes. This review evaluates the evidence for convergence of diet- and stress-responsive pathways at the intestinal barrier and their possible relevance to metabolic inflammation.

Activation of the hypothalamic-pituitary-adrenal (HPA) and sympatho-adrenomedullary axes, together with adverse dietary exposures, converges on the gut microbiota and epithelial barrier. Stress-related corticotropin-releasing hormone/mast-cell signalling, glucocorticoids, and catecholamines can remodel mucus and tight junctions, while high-fat, Western-style, ultra-processed, or prolonged substrate-restricted diets reduce butyrogenic support and may shift bile-acid metabolism toward barrier-disruptive secondary bile acids. The resulting mucus erosion and tight-junction remodelling, including reduced occludin/ZO-1 and increased pore-forming claudin-2, increase permeability and facilitate lipopolysaccharide translocation. LPS-TLR4-NF-κB signalling provides inflammatory priming and can converge with diet- and stress-related danger signals on the NLRP3 inflammasome, promoting IL-1β, TNF-α, and IL-6 release. These pathways plausibly contribute to obesity, insulin resistance, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease, although direct human evidence for a true diet × stress barrier interaction remains limited.

Preclinical studies provide mechanistic support for overlapping diet- and stress-responsive barrier pathways, and acute human stress studies provide functional permeability evidence. Human dietary evidence is more often indirect, and direct factorial studies of diet × stress effects on barrier function are largely absent. The proposed framework should therefore be treated as a testable synthesis rather than an established causal model.